PROJECT SUMMARY/ABSTRACT Attacks of myelin oligodendrocyte glycoprotein antibody disease (MOGAD) can render a patient blind, paralyzed or comatose and distinguishing it from other demyelinating diseases such as multiple sclerosis (MS) and aquaporin-4(AQP4)-IgG positive neuromyelitis optica spectrum disorder (NMOSD) is crucial given the major differences in clinical course, treatment and prognosis. Major knowledge gaps in MOGAD are hindering patient care and a barrier to understanding its pathogenesis. The absence of MOGAD incidence and prevalence data and limited knowledge on its epidemiology worldwide directly impacts decisions on when to order MOG-IgG, healthcare planning, clinical trial design and identification of risk factors. The lack of prospective USA data regarding the prognostic value of MOG-IgG titer and persistence impacts treatment decisions. MOG-IgG in cerebrospinal fluid (CSF) is used by clinicians to diagnose MOGAD, yet data on its diagnostic utility is limited compared to the established utility of serum MOG-IgG. The limited data on MRI evolution and immuno-pathology hinders our understanding of MOGAD pathogenesis. The long-term goal is to better diagnose, treat, and understand MOGAD. The objective of this proposal is to determine the incidence and prevalence of MOGAD, the prognostic value of MOG-IgG testing, the diagnostic utility of CSF MOG-IgG, the evolution of MRI lesions and the immunopathology. The central hypotheses (supported by the applicants preliminary data) is that MOGAD epidemiology is similar to AQP4-IgG in the USA but varies by region, that serum MOG-IgG persistence and high titer predict relapse, that CSF MOG-IgG lacks diagnostic utility, that MOGAD MRI lesions resolve more often than MS and that immuno-pathological characteristics of MOGAD can be defined. The rationale is that these findings will directly impact patient care, facilitate clinical trial readiness, enhance understanding of pathogenesis, and lead to development of novel treatments. The hypothesis will be tested by pursuing three specific aims: 1) To determine the population-based incidence, prevalence and frequency of MOGAD versus AQP4-IgG and MS across multiple world regions; 2) To identify the prognostic value of MOG-IgG titer and persistence, assess the utility of CSF MOG-IgG and compare MRI evolution to MS and AQP4-IgG NMOSD; 3) To define the immuno-pathology of MOGAD and compare it to MS and AQP4-IgG NMOSD. To do this we will utilize the largest clinical, sero-epidemiologic and pathologic biobank of demyelinating disease in the world. The approach is innovative because it uses a novel live-cell flow cytometry based MOG-IgG assay developed by the team of applicants. The proposed research is significant because it is expected to guide resource allocation, directly impact patient care by providing guidance on diagnostics and therapeutics and give insight into pathogenesis. Ultimately, the knowledge of immunopathology may lead to the development of novel treatments similar to how complement deposition in AQP4-IgG NMOSD pathology led to phase 2 and 3 trials showing efficacy and safety of eculizumab (a complement inhibitor).